Inhibitory actions of endothelin-1 on pain processing.
ABSTRACT Endothelin-1 (ET-1) in the central nervous system has been suggested to produce suppressive effects on pain transmission. We investigated the manner by which ET-1 exerts this action. ET-1 administered intracerebroventricularly produced a dose-dependent antinociceptive effect in a thermal pain test that utilized a spinal reflex to determine nociceptive thresholds. This suggested that the antinociceptive effect of ET-1 involved a descending pain inhibitory system. The antinociceptive effect was blocked by an ETA receptor antagonist but not by an ETB receptor antagonist, indicating that the action was mediated through the ETA receptor. Antagonists of opioid receptors, serotonin receptors, alpha-2 adrenergic receptors, oxytocin receptors, and dopamine receptors did not block the antinociceptive effect of ET-1. Thus, major descending inhibitory systems were probably not involved. The antinociceptive effect was blocked by intracerebroventricular administration of an alpha-1 adrenergic receptor antagonist. This indicated that the antinociceptive effect involved the activation of a supraspinal noradrenergic pathway, which in turn may activate a still unknown descending pain inhibitory system.
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ABSTRACT: A differential role of endothelin-1 (ET-1) in pain processing has recently been suggested. However, the function of central ET-1 in neuropathic pain (NP) has not been fully elucidated to date. We report here the action of endogenous central ET-1 in sciatic nerve ligation-induced NP (SNL-NP) in a transgenic animal model that over-expresses ET-1 in the astrocytes (GET-1 mice). We hypothesized that the over-expression of astrocytic ET-1 would exert anti-allodynic and anti-hyperalgesic effects in NP, as demonstrated by mechanical threshold and plantar withdrawal latency using the von Frey filament and heat stimuli. In our animal model, GET-1 mice showed an increase in the withdrawal threshold and latency in response to the mechanical and thermal stimuli, respectively, in pain behavior tests after SNL. ET-1 and endothelin type A receptor (ETA-R) levels were increased significantly in L4-L6 segments of the spinal cord (ipsilateral to SNL) of GET-1 mice at 7 and 21 days after surgery. Moreover, intrathecal administration of a specific ETA-R antagonist, BQ-123, attenuated the anti-allodynic and anti-hyperalgesic phenotype in GET-1 mice. The effects of BQ-123 on the mRNA expression of extracellular signal-regulated protein kinase1/2 (ERK1/2) and protein kinase B/serine protein kinase (Akt(s)) were assessed in the ipsilateral L4-L6 segments harvested 30 minutes after BQ-123 administration on day 7 after surgery. Phosphorylation of ERK1/2 and Akt(s) in the ipsilateral spinal cord of GET-1 mice was reduced following SNL, whereas no reduction was observed after intrathecal injection of BQ-123. In conclusion, our results showed that the over-expression of astrocytic ET-1 reduced SNL-induced allodynia and hyperalgesia by inhibiting the activation of ERK1/2 and Akt(s) via the ETA-R-mediated pathway.Molecular and Cellular Neuroscience 01/2014; · 3.84 Impact Factor
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ABSTRACT: Endothelin-1 (ET-1) predominates in the endothelin family effectively in vascular tone control, mitogenesis, and neuromodulation. Its receptors are widespread in the central nervous system (CNS) associated with endogenous pain control, suggesting an important role of ET-1 in central pain processing. This study aimed to evaluate the effect of central ET-1 on the development of neuropathic pain behaviour by repeated intrathecal administration of endothelin type A receptor (ETAR) antagonist (BQ-123) in a sciatic nerve ligation (SNL) animal model. BQ-123 was administered intrathecally to rats at dosages 15 μ g, 20 μ g, 25 μ g, and 30 μ g, daily for 3 days. Mechanical allodynia was assessed daily 30 minutes before/after injection, 1 hour after injection of BQ-123 from post-SNL day 4 to day 6, and once on day 7 (without BQ-123 administration) before rats were sacrificed. Increasing trends of mechanical threshold were observed, and they reached significance at all dosages on post-SNL day 7 (P < 0.05 at dosage 15 μ g and P < 0.001 at dosages 20 μ g, 25 μ g, and 30 μ g) in comparison to control group. BQ-123 at dosage 30 μ g showed the most stable and significant mechanical threshold rise. Repeated central administration of BQ-123 alleviated mechanical allodynia after SNL. Our results provide insight into the therapeutic strategies, including timing, against neuropathic pain development with ETAR antagonist.BioMed research international. 01/2013; 2013:529871.
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ABSTRACT: Endothelin-1 is known to be a potent vasoconstrictor. Administration of endothelin-1 to the central nervous system (CNS) induces antinociceptive effects. Nociceptive stimuli affect dorsal root ganglion (DRG) neurons and neurons/astrocytes/microglia in the dorsal horn of the spinal cord. Surgical incision in the plantar aspect of the rat hindpaw is a model for postoperative pain, and withdrawal thresholds reportedly decrease around the incision. We hypothesized that intrathecal endothelin-1 would have antinociceptive effects in this model, and affect DRG neurons and microglia/neurons in the dorsal horn. Intrathecal endothelin-1 partially restored the withdrawal threshold (which was decreased by plantar incision). BQ-123, and BQ-788 (specific endothelin ET(A)- and ET(B)-receptor antagonists, respectively) attenuated the increase in withdrawal threshold induced by endothelin-1. Phosphorylation of extracellular signal-regulated kinase (ERK) in DRG neurons and microglial activation/ERK phosphorylation in the dorsal horn were observed following the incision. Endothelin-1 decreased the incision-induced increase in the numbers of phosphorylated ERK-positive neurons in DRG and activated microglia in the dorsal horn, without affecting the numbers of phosphorylated ERK-positive neurons in the dorsal horn. BQ-123 or BQ-788 partially suppressed these endothelin-1-induced alterations. Our results show that the pain threshold, which is decreased by surgical stimuli, is partially restored by intrathecal endothelin-1 through both endothelin ET(A)- and ET(B)- receptors in DRG neurons and microglia in the spinal cord. Endothelin-1 administration to the CNS may be worth considering as a new candidate for the treatment of postoperative pain and to mitigate prolonged periods of pain.European journal of pharmacology 10/2012; · 2.59 Impact Factor